Estrogen-Induced Cholestasis Leads to Repressed CYP2D6 Expression in CYP2D6-Humanized Mice

Abstract

Cholestasis activates bile acid receptor farnesoid X receptor (FXR) and subsequently enhances hepatic expression of small heterodimer partner (SHP). We previously demonstrated that SHP represses the transactivation of cytochrome P450 2D6 (CYP2D6) promoter by hepatocyte nuclear factor (HNF) 4a. In this study, we investigated the effects of estrogeninduced cholestasis on CYP2D6 expression. Estrogen-induced cholestasis occurs in subjects receiving estrogen for contraception or hormone replacement, or in susceptible women during pregnancy. In CYP2D6-humanized transgenic (Tg-CYP2D6) mice, cholestasis triggered by administration of 17a-ethinylestradiol (EE2) at a high dose led to 2-to 3-fold decreases in CYP2D6 expression. This was accompanied by increased hepatic SHP expression and subsequent decreases in the recruitment of HNF4a to CYP2D6 promoter. Interestingly, estrogen-induced cholestasis also led to increased recruitment of estrogen receptor (ER) a, but not that of FXR, to Shp promoter, suggesting a predominant role of ERa in transcriptional regulation of SHP in estrogen-induced cholestasis. EE2 at a low dose (that does not cause cholestasis) also increased SHP (by ∼50%) and decreased CYP2D6 expression (by 1.5-fold) in Tg-CYP2D6 mice, the magnitude of differences being much smaller than that shown in EE2-induced cholestasis. Taken together, our data indicate that EE2-induced cholestasis increases SHP and represses CYP2D6 expression in Tg-CYP2D6 mice in part through ERa transactivation of Shp promoter.

Does In Vitro Cytochrome P450 Downregulation Translate to In Vivo Drug‐Drug Interactions? Preclinical and Clinical Studies With 13‐cis‐Retinoic Acid

“…Together with the literature results, our findings suggest that the effects of retinoids on CYPs are complex and involve multiple nuclear receptors. 8,32,33 It is possible that endogenous regulators of these pathways in vivo, such as bile acids, and stellate cell and Kupffer cell-derived factors, are not well represented in vitro resulting in IVIVE disconnect. Induction of Cyp2d in mice and CYP2D6 in the clinical study is in agreement with the observed increase in Cyp2d11, Cyp2d22, Cyp2d26, and Cyp2d40 mRNA and activity in mice during pregnancy and corresponding increase in RA signaling in the maternal liver during pregnancy.…”

The Influence of CYP2D6 Phenotype on the Pharmacokinetic Profile of Atomoxetine in Caucasian Healthy Subjects

“…Female subjects using oral contraceptives can be considered a potential interfering factor for this analysis due to the fact that hormones such as progesterone, testosterone, pregnanolone, pregnenolone, 17β-estradiol, and 17β-hydroxyprogesterone competitively inhibit CYP2D6 activity, whereas epiallopregnanolone and alfaxalone noncompetitively inhibit the same isoenzyme [24]. In addition, pharmacological studies revealed that estrogen-induced cholestasis can repress CYP2D6 expression and activity [25]. However, although the study protocol did permit the use of oral contraceptives during the clinical trial, an enquiry revealed that 50 % of the female subjects were using bar- AUC_ATX -area under the plasma concentration-time curve from time 0 to infinity for atomoxetine; AUC_HATX-gluc -area under the plasma concentration-time curve from time 0 to infinity for 4-hydroxyatomoxetine-O-glucuronide; MR_ AUC-metabolic ratio calculated as AUC_ATX / AUC_HATX-gluc rier contraceptive methods, while the rest did not report the use of any birth control method.…”

Determinants of Cytochrome P450 2D6 mRNA Levels in Healthy Human Liver Tissue

“…Significant association between CYP2D6 mRNA and activity levels was reported in human liver tissue . In addition, studies using CYP2D6 ‐humanized mice showed that transcriptional regulation of CYP2D6 can lead to serial changes in CYP2D6 protein and activity levels …”

“…Genetic polymorphisms of CYP2D6 linked to no enzyme activity are known to contribute to the poor metabolizer, whereas increased copy number of normal function CYP2D6 alleles is associated with ultrarapid metabolizer phenotypes . Of interest, recent studies indicate that differential transcriptional regulation of CYP2D6 may in part explain the variability in CYP2D6‐mediated drug metabolism . Significant association between CYP2D6 mRNA and activity levels was reported in human liver tissue .…”

“…In addition to bile acids, retinoids induce SHP expression . Pharmacological or pathological induction of SHP (e.g., retinoid administration or cholestasis) was shown to trigger CYP2D6 downregulation in CYP2D6 ‐humanized mice by inhibiting HNF4α transactivation of the CYP2D6 promoter …”